Towards clinical translation of nanomedicines: Formulation scale-up and model systems.

Non-viral nanomedicines, including nanoparticles (NPs) composed of lipids and polymers, represent a transformative approach to drug and gene therapy. However, clinical translation of these technologies is limited by two key barriers: the scale-up of NP formulations and the challenge of conducting predictive preclinical studies in relevant animal models. Efficient upscaling of nanomedicines, from cost and material requirement perspectives, requires manufacturing processes that can reliably provide products across the many orders of magnitude of scale from discovery (<mg of product) to large-scale testing (>kg of product). Additionally, initial preclinical studies are often performed in mouse models for discovery; however, mid- to large-size animal models such as rabbits, pigs, sheep, and nonhuman primates are more relevant to human scale and physiology in the context of evaluating the safety, efficiency, and efficacy of therapeutic strategies proposed for use in humans across age groups. This review summarizes some current strategies to scale-up the production of nanomedicines for translational investigations. Animal models and new approach methodologies are also addressed for NP assessment and screening, including the physiological distinctions when comparing rodent models to larger species that can impact NP delivery. Current challenges are also highlighted in terms of scale-up and preclinical validation with the objective of highlighting scalable, effective nanomedicine platforms that can be considered for translation to human trials.